Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/04—Macromolecular materials
  • A61L31/048—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea

Definitions

• This invention is directed to improved ophthalmic and otorhinolaryngological device materials.
• this invention relates to soft, high refractive index acrylic device materials that have improved glistening resistance.
• hydrogels With the recent advances in small-incision cataract surgery, increased emphasis has been placed on developing soft, foldable materials suitable for use in artificial lenses. In general, these materials fall into one of three categories: hydrogels, silicones, and acrylics.
• hydrogel materials have a relatively low refractive index, making them less desirable than other materials because of the thicker lens optic necessary to achieve a given refractive power.
• Conventional silicone materials generally have a higher refractive index than hydrogels, but tend to unfold explosively after being placed in the eye in a folded position. Explosive unfolding can potentially damage the corneal endothelium and/or rupture the natural lens capsule.
• Acrylic materials are desirable because they typically have a high refractive index and unfold more slowly or controllably than conventional silicone materials.
• U.S. Pat. No. 5,290,892 discloses high refractive index, acrylic materials suitable for use as an intraocular lens (“IOL”) material. These acrylic materials contain, as principal components, two aryl acrylic monomers. The IOLs made of these acrylic materials can be rolled or folded for insertion through small incisions.
• IOL intraocular lens
• U.S. Pat. No. 5,331,073 also discloses soft acrylic IOL materials. These materials contain as principal components, two acrylic monomers which are defined by the properties of their respective homopolymers. The first monomer is defined as one in which its homopolymer has a refractive index of at least about 1.50. The second monomer is defined as one in which its homopolymer has a glass transition temperature less than about 22° C. These IOL materials also contain a cross-linking component. Additionally, these materials may optionally contain a fourth constituent, different from the first three constituents, which is derived from a hydrophilic monomer. These materials preferably have a total of less than about 15% by weight of a hydrophilic component.
• U.S. Pat. No. 5,693,095 discloses foldable, high refractive index ophthalmic lens materials containing at least about 90 wt. % of only two principal components: one aryl acrylic hydrophobic monomer and one hydrophilic monomer.
• the aryl acrylic hydrophobic monomer has the formula
• X is H or CH 3 ;
• Flexible intraocular lenses may be folded and inserted through a small incision.
• a softer material may be deformed to a greater extent so that it can be inserted through an increasingly smaller incision.
• Soft acrylic or methacrylic materials typically do not have an appropriate combination of strength, flexibility and non-tacky surface properties to permit IOLs to be inserted through an incision as small as that required for silicone IOLs.
• Polyethylene glycol (PEG) dimethacrylates are known to improve glistening resistance of hydrophobic acrylic formulations. See, for example, U.S. Pat. Nos. 5,693,095; 6,528,602; 6,653,422; and 6,353,069. Both the concentration and molecular weight of PEG dimethacrylates have an impact on glistening performance. Generally, use of higher molecular weight PEG dimethacrylates (1000 MW) yield copolymers with improved glistening performance at low PEG concentrations (10-15 wt %), as compared to lower molecular weight PEG dimethacrylates ( ⁇ 1000 MW). However, low PEG dimethacrylate concentrations are desirable to maintain a high refractive index copolymer. Addition of PEG dimethacrylates also tends to decrease the modulus and tensile strength of the resulting copolymer. Also, higher molecular weight PEG dimethacrylates are generally not miscible with hydrophobic acrylic monomers.
• Improved soft, foldable acrylic device materials which are particularly suited for use as IOLs, but which are also useful as other ophthalmic or otorhinolaryngological devices, such as contact lenses, keratoprostheses, corneal rings or inlays, otological ventilation tubes and nasal implants, have been discovered.
• These polymeric materials comprise an alkylphenol ethoxylate monomer.
• the present invention is based on the finding that use of alkylphenol ethoxylate monomers in acrylic intraocular lens formulations reduces or eliminates temperature-induced glistening formation in hydrophobic acrylic copolymers.
• the subject monomers allow synthesis of glistening resistant, low equilibrium water content, high refractive index IOLs.
• the device materials of the present invention are copolymers comprising a) a monofunctional acrylate or methacrylate monomer [1], b) a difunctional acrylate or methacrylate cross-linker [2], and c) a functionalized alkylphenol ethoxylate [3].
• the device materials may contain more than one monomer [1], more than one monomer [2], and more than one monomer [3].
• references to each ingredient are intended to encompass multiple monomers of the same formula and references to amounts are intended to refer to the total amount of all monomers of each formula.
• Preferred monomers of formula [1] are those wherein:
• Monomers of formula [1] are known and can be made by known methods. See, for example, U.S. Pat. Nos. 5,331,073 and 5,290,892. Many monomers of formula [1] are commercially available from a variety of sources. Preferred monomers of formula [1] include benzyl methacrylate; 2-phenylethyl methacrylate; 3-phenylpropyl methacrylate; 4-phenylbutyl methacrylate; 5-phenylpentyl methacrylate; 2-phenoxyethyl methacrylate; 2-(2-phenoxyethoxy)ethyl methacrylate; 2-benzyloxyethyl methacrylate; 2-(2-(benzyloxy)ethoxy)ethyl methacrylate; and 3-benzyloxypropyl methacrylate; and their corresponding acrylates.
• Monomers of formula [2] are known and can be made by known methods, and are commercially available.
• Preferred monomers of formula [2] include ethylene glycol dimethacrylate (“EGDMA”); diethylene glycol dimethacrylate; triethylene glycol dimethacrylate; 1,6-hexanediol dimethacrylate; 1,4-butanediol dimethacrylate; 1,4-benzenedimethanol dimethacrylate; and their corresponding acrylates. Most preferred is 1,4-butanediol diacrylate.
• Monomers of formula [3] can be made by known methods.
• such monomers may be made by esterification reactions involving, for example, the alkylphenol ethoxylate alcohol and suitable carboxylic acids, acyl halides, or carboxylic acid anhydrides.
• the alkylphenol ethoxylate can be heated with a carboxylic acid or carboxylic acid alkyl ester in the presence of a catalyst to form the desired ester, with water or low boiling alcohol as a byproduct which can be removed to drive the reaction to completion.
• the alkylphenol ethoxylate can also be treated with an acyl halide in the presence of a base such as triethylamine which serves as a hydrohalide acceptor.
• the alkylphenol ethoxylate can also be treated with a carboxylic acid anhydride in the presence of a base such as triethylamine or pyridine which catalyzes the reaction and neutralizes the acid formed.
• the copolymeric materials of the present invention contain a total amount of monomer [1] from 75 to 97%, preferably from 80 to 95%, and most preferably from 80-93%.
• the difunctional cross-linker [2] concentration is generally present in an amount from 0.5-3%, and preferably 1-2%.
• the materials of the present invention have at least one monomer [3].
• the total amount of monomer [3] depends on the desired physical properties for the device materials.
• the copolymeric materials of the present invention contain a total of at least 1% and can contain as much as 20% of monomer [3].
• the copolymeric device materials will contain from 1 to 15% of monomer [3].
• the device materials will contain from 1 to 10% of monomer [3].
• the copolymeric device material of the present invention optionally contains one or more ingredients selected from the group consisting of a polymerizable UV absorber and a polymerizable colorant.
• the device material of the present invention contains no other ingredients besides the monomers of formulas [1] and [2], the monomer [3], and the optional polymerizable UV absorbers and colorants.
• the device material of the present invention optionally contains reactive UV absorbers or reactive colorants.
• reactive UV absorbers are known.
• a preferred reactive UV absorber is 2-(2′-hydroxy-3′-methallyl-5′-methylphenyl)benzotriazole, commercially available as o-Methallyl Tinuvin P (“oMTP”) from Polysciences, Inc., Warrington, Pa.
• UV absorbers are typically present in an amount from about 0.1-5%.
• Suitable reactive blue-light absorbing compounds include those described in U.S. Pat. No. 5,470,932. Blue-light absorbers are typically present in an amount from about 0.01-0.5%.
• the device materials of the present invention preferably contain both a reactive UV absorber and a reactive colorant.
• the chosen ingredients [1], [2], and [3], along with any of the optional ingredients, are combined and polymerized using a radical initiator to initiate polymerization by the action of either heat or radiation.
• the device material is preferably polymerized in de-gassed polypropylene molds under nitrogen or in glass molds.
• Suitable polymerization initiators include thermal initiators and photoinitiators.
• Preferred thermal initiators include peroxy free-radical initiators, such as t-butyl(peroxy-2-ethyl)hexanoate and di-(tert-butylcyclohexyl) peroxydicarbonate (commercially available as Perkadox® 16 from Akzo Chemicals Inc., Chicago, Ill.).
• preferred photoinitiators include benzoylphosphine oxide initiators, such as 2,4,6-trimethyl-benzoyldiphenyl-phosphine oxide, commercially available as Lucirin® TPO from BASF Corporation (Charlotte, N.C.). Initiators are typically present in an amount equal to about 5% or less of the total formulation weight, and more preferably less than 2% of the total formulation. As is customary for purposes of calculating component amounts, the initiator weight is not included in the formulation weight % calculation.
• the device materials of the present invention are used to make IOLs having an optic diameter of 5.5 or 6 mm that are designed to be compressed or stretched and inserted through surgical incision sizes of 2 mm or less.
• the monomer [3] is combined with at least one mono-functional acrylate or methacrylate monomer [1] and a multifunctional acrylate or methacrylate cross-linker [2] and copolymerized using a radical initiator in a suitable lens mold.
• the device material preferably has a refractive index in the hydrated state of at least about 1.50, and more preferably at least about 1.53, as measured by an Abbe' refractometer at 589 nm (Na light source) and 25° C.
• Optics made from materials having a refractive index lower than 1.50 are necessarily thicker than optics of the same power which are made from materials having a higher refractive index.
• IOL optics made from materials with comparable mechanical properties and a refractive index lower than about 1.50 generally require relatively larger incisions for IOL implantation.
• the proportions of the monomers to be included in the copolymers of the present invention should be chosen so that the copolymer has a glass transition temperature (T g ) not greater than about 37° C., which is normal human body temperature.
• T g glass transition temperature
• Copolymers having glass transition temperatures higher than 37° C. are not suitable for use in foldable IOLs; such lenses could only be rolled or folded at temperatures above 37° C. and would not unroll or unfold at normal body temperature.
• T g is measured by differential scanning calorimetry at 10° C./min., and is determined at the midpoint of the transition of the heat flux curve.
• the materials of the present invention must exhibit sufficient strength to allow devices made of them to be folded or manipulated without fracturing.
• the copolymers of the present invention will have an elongation of at least 80%, preferably at least 100%, and most preferably between 110 and 200%. This property indicates that lenses made of such materials generally will not crack, tear or split when folded. Elongation of polymer samples is determined on dumbbell shaped tension test specimens with a 20 mm total length, length in the grip area of 4.88 mm, overall width of 2.49 mm, 0.833 mm width of the narrow section, a fillet radius of 8.83 mm, and a thickness of 0.9 mm.
• the strain is set to zero and the test begun.
• the modulus is calculated as the instantaneous slope of the stress-strain curve at 0% strain (“Young's modulus”), 25% strain (“25% modulus”) and 100% strain (“100% modulus).
• IOLs made of the ophthalmic device materials of the present invention are more resistant to glistenings than other materials.
• Glistenings are measured according to the following test. The presence of glistenings is measured by placement of a lens or disk sample into a vial or sealed glass chamber and adding deionized water or a balanced salt solution. The vial or glass chamber is then placed into a water bath preheated to 41° C. Samples are to be maintained in the bath for a minimum of 16 hours and preferably 24 ⁇ 2 hours. The vial or glass chamber is then immediately placed in a water bath preheated to 35° C. and allowed to equilibrate at 35° C. for a minimum of 30 minutes and preferably 30 to 60 minutes.
• the sample is inspected visually in various on angle or off angle lighting to evaluate clarity while at 35° C. Visualization of glistenings is carried out at 35° C. with light microscopy using a magnification of 50 to 200 ⁇ .
• a sample is judged to have many glistenings if, at 50-200 ⁇ magnification, there are approximately 50 to 100% as many glistenings as observed in control samples based on 65 weight % PEA, 30 weight % PEMA, 3.2 weight % BDDA, and 1.8 weight % OMTP.
• a sample is judged to have few glistenings if there are approximately 10% or more glistenings relative to the quantity observed in control samples.
• a sample is judged to have very few glistenings if there are approximately 1% or more glistenings relative to a control sample.
• a sample is judged to be free of glistenings if the number of glistenings detected in the eyepiece is zero.
• a sample is judged to be substantially free of glistenings if the number of glistenings detected in the eyepiece is less than about 2/mm 3 .
• the sample is rastered throughout the entire volume of the lens, varying the magnification levels (50-200 ⁇ ), the aperture iris diaphragm, and the field conditions (using both bright field and dark field conditions) in an attempt to detect the presence of glistenings.
• the copolymers of the present invention preferably have an equilibrium water content (EWC) of 0.5 to 3 weight %.
• EWC is measured by placing one rectangular 0.9 ⁇ 10 ⁇ 20 mm slab in a 20 ml scintillation vial filled with deionized water and subsequently heating in a 35+ C. water bath for a minimum of 20 hours and preferably 48 ⁇ 8 hours. The slab is blotted dry with lens paper and the % water content is calculated as follows:
• the IOLs constructed of the device materials of the present invention can be of any design capable of being stretched or compressed into a small cross section that can fit through a 2-mm incision.
• the IOLs can be of what is known as a one-piece or multi-piece design, and comprise optic and haptic components.
• the optic is that portion which serves as the lens and the haptics are attached to the optic and are like arms that hold the optic in its proper place in the eye.
• the optic and haptic(s) can be of the same or different material.
• a multi-piece lens is so called because the optic and the haptic(s) are made separately and then the haptics are attached to the optic.
• the optic and the haptics are formed out of one piece of material. Depending on the material, the haptics are then cut, or lathed, out of the material to produce the IOL.
• the materials of the present invention are also suitable for use as other ophthalmic or otorhinolaryngological devices such as contact lenses, keratoprostheses, corneal inlays or rings, otological ventilation tubes and nasal implants.
• IEMA 2-isocyanatoethyl methacrylate
• stannous octoate Aldrich
• IEMA 2-isocyanatoethyl methacrylate
• IEMA 2-isocyanatoethyl methacrylate
• IEMA 2-isocyanatoethyl methacrylate
• TergNP4-MA TergNP4-MA.
• IEMA 2-isocyanatoethyl methacrylate
• IEMA 2-isocyanatoethyl methacrylate
• IEMA 2-isocyanatoethyl methacrylate
• TergNP4-TMI TergNP4-TMI.
• 5.11 g (12.1 mmol) of TergitolTM NP-4 and 10 mg MEHQ (Aldrich, Milwaukee, Wis.) were dissolved in 100 ml anhydrous THF (Aldrich) in a 250 ml round bottom flask equipped with magnetic stirrer and nitrogen inlet.
• 2.54 g (12.6 mmol) of 3-isopropenyl-alpha,alpha-dimethylbenzyl isocyanate (TMI) (Aldrich) and 10 mg dibutyltin dilaurate (Aldrich) were added and the reaction mixture was heated to 60° C. for 20 hours under a nitrogen blanket.
• the solvent was removed via rotary evaporation and the resulting liquid was further dried under vacuum ( ⁇ 0.1 mm Hg) for 20 hours.
• the refractive index values and molecular weights of the starting alkyllphenol ethoxylate alcohols were measured prior to functionalizing with reactive groups as shown in Table 1. Refractive index values were measured at 35° C. GPC number average molecular weights were measured in THF relative to polystyrene standards. Number average molecular weight values were also estimated using a Bruker 400 MHz NMR spectrometer using CD 2 Cl 2 as solvent. Equivalent weights were determined using a modified hydroxyl number (OH#) test method in which 2-3 grams of alkylphenol ethoxylate were treated with acetic anhydride in pyridine to give a mixture of the alkylphenol ethoxylate acetate and acetic acid.
• OH# modified hydroxyl number
• reaction components listed in Tables 2-4 except for AIBN, were mixed together with stirring or shaking for at least 30 minutes at 23° C., until all components were dissolved.
• the AIBN was subsequently added and the reaction mixture was stirred for a minimum of 5 minutes, until the initiator was dissolved.
• the reactive components are reported in grams.
• the reactive components were purged for approximately 15 minutes using N 2 and placed inside a low humidity N 2 purged glove box.
• the reactive components were syringed or pipetted onto clean polypropylene mold halves containing 1 ⁇ 10 ⁇ 20 mm rectangular wells and then covered with the complementary flat polypropylene mold halves.
• the mold halves were compressed using binder clips and the mixtures were cured at 70° C. for 16 hours using a Yamato DKN400 constant temperature oven.
• the molds were allowed to cool to room temperature.
• the top mold halves were removed and the rectangular polymer slabs were removed from the wells with tweezers and placed individually in 38 ⁇ 8 mm Histo Plas tissue processing capsules (Bio Plas Inc., San Rafael, Calif.).
• the slabs were extracted in acetone for a minimum of 16 hours and then air dried at ambient temperature for 20 hours, followed by high vacuum ( ⁇ 0.1 mm Hg) at ambient temperature for 20 hours, and high vacuum at 70° C. for 20 hours.
• % ⁇ ⁇ extractables ( non ⁇ - ⁇ extracted ⁇ ⁇ weight - extracted ⁇ ⁇ weight ) non ⁇ - ⁇ extracted ⁇ ⁇ weight ⁇ 100
• the equilibrium water content (EWC) was measured by placing one slab in a 20 ml scintillation vial filled with deionized water and subsequently heating in a 35° C. water bath for a minimum of 20 hours. The slab was blotted dry with lens paper and the % water content was calculated as follows:
• the extent of glistening formation was evaluated by carrying out a 41° to 35° C. change in temperature ( ⁇ T) test.
• ⁇ T change in temperature
• samples were first placed in 20 ml scintillation vials containing deionized water and heated at 41° C. for a minimum of 20 hours.
• the entire cross section ( ⁇ 200 mm 2 ) of samples was examined for glistening formation approximately 30 to 60 minutes after cooling to ambient temperature using an Olympus BX60 microscope equipped with a 10 ⁇ objective.
• the number of glistening was counted visually at 3 different points along the slab, typically in the center and approximately 2, 5, and 7 mm from the left edge.
• the samples were also visually inspected for haze after the ⁇ T test.
• Examples 13A through 13P show that the reaction mixture components and their amounts may be varied. All materials were clear and showed low haze prior to contact with water. Examples 13B through 13D showed noticeable haze after equilibrating in deionized water at 41° C. followed by cooling to 35° C.
• the refractive index values were generally high, between 1.54 and 1.55 for all examples.
• EWCs equilibrium water contents at 35° C. were less than 1.0% for Examples 13A through 13N, which contained functionalized alkylphenol ethoxylates with between 1 and 15 ethylene oxide repeat units. EWC values of 1.5% were observed for Examples 130 and 13P, which contained functionalized alkylphenol ethoxylates with an average of 40 ethylene oxide repeat units.

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